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“The role of ALC1, a novel ATP-dependent chromatin remodelling protein, in transcriptional regulation, tumorigenesis and neurodegeneration”

Final Report Summary - CHROMALC1HCC (“The role of ALC1, a novel ATP-dependent chromatin remodelling protein, in transcriptional regulation, tumorigenesis and neurodegeneration”)

ALC1 (also known as CHD1L) is a member of the SWI/SNF family of ATP-dependent chromatin remodelling complexes (such as Snf2, ISWI and CHD1) (Flaus et al., 2006). ALC1 contains a carboxy-terminal macrodomain that is necessary and sufficient for binding to poly(ADP-ribose) and an ATPase domain in the N-terminus. Recent work from the Boulton lab has shown that ALC1 is recruited to DNA breaks upon laser micro-irradiation via macro domain interactions with sites of active PAR synthesis. ALC1 depletion in cells leads to a defect in DNA repair of both double (DSBs) and single strand breaks (SSBs) (Ahel, et al., 2009).
hALC1 was recently identified as a target oncogene within the 1q21 amplicon, which is the most frequent genetic alteration in human hepatocellular carcinoma (HCC) and occurs in 58%-78% of primary HCC cases. Hepatocellular Carcinoma is the most aggressive liver tumour, one of the most frequent cancers in East Asia and Africa and ranks as the third most common cause of cancer mortality worldwide. Infection with hepatitis B and C virus is a major risk factor for HCC in developed countries (El-Serag and Rudolph, 2007). Emerging evidences indicate that there are other important life style factors that contribute to HCC development, such as diabetes and obesity that induce chronic inflamation and cirrhosis, thus leading to liver tumor development (Park et al., 2010). Nowadays, the only effective treatment for patients with HCC is surgery and hepatectomy, nevertheless it cannot always be performed. The administration of Sorafenib, a multikinase inhibitor, in patients with advanced HCC has shown an overall suvival of 3 months with respect to placebo-treated patients, and also shows severe secondary effects such as diarrhea, weight loss, hand-foot skin reaction and hypophosphatemia (Llovet et al., 2008). The absence of a successful therapy for HCC prophilaxis and treatment requires a big effort in basic and clinical research to find specific molecules to be pharmacologically applied to prevent the initiation and the development of HCC.
Our main goal since I have started the project is to study the role of ALC1 in homeostasis and diseases. Among different diseases, cancer is the one that we were focus on from the very beginning. There were some previous data demonstrating that ALC1 drives liver tumour, nevertheless the molecular mechanism by which it drives cancer initiation and/or development remains unclear.